Substituted 3-phenyl hydantoins useful as fungicides

ABSTRACT

The hydantoin derivatives of the formula:   WHEREIN Ar represents phenyl, or phenyl carrying substituents selected from halogen, alkyl, alkoxy and trifluoromethyl, R1 represents alkoxy or a grouping -NR3R4, in which R3 and R4 represent hydrogen, alkyl or alkenyl, R2 represents hydrogen or alkyl, and X represents oxygen or sulphur, possess fungicidal properties.

States atent [191 Aug. 28, 1973 SUBSTITUTED 3-PHENYL HYDANTOINS USEFULAS FUNGICIDES [75] Inventor: Michel Sauli, Paris, France [73] Assignee:Rhone-Poulenc S.A., Paris, France [22] Filed: Oct. 5, 1971 [21] App].No.: 186,772

[30] Foreign Application Priority Data OTHER PUBLICATIONS Biltz et a1.,Chem. Abst., Vol. 21, pages 3351-3352 (1927). QD1.A51

Bornwater, Chem. Abst., Vol. 6, pages 2743-2744 (1912). QD1.A51

Farbwerke I-loechst, Chem. Abst., V01. 72, No. 89756h (1970). QDl.A51

Freter et al., Chem. Abst., V01. 52, Columns 8125-8126(1958).QD1.A51

Johnson et a1., Chem. Abst., V01. 7, pages 3508-3509 (1913). QD1.A51

Reeve et a1., Chem. Abst., V01. 71,No. 13057q (1969). QD1.A51

Stark, Chem. Abst., Vol. 63, Column 18516 (1965). QD1.A51

Swan, Chem. Abst., Vol. 47, column 9274 (1953). QD1.A51 Umemoto, Chem.Abst., Vol. 61, Column 8296 (1964). QD1.A51

Murray, Chem. Abst., Vol. 71, No. 14440w (1969)v QD1.A51

Primary Examiner-Natalie Trousof A!t0rneyStevens, Davis, Miller andMosher [57] ABSTRACT The hydantoin derivatives of the formula:

wherein Ar represents phenyl, or phenyl carrying substituents selectedfrom halogen, alkyl, alkoxy and trifluoromethyl, R, represents alkoxy ora grouping NR R in which R and R represent hydrogen, alkyl or alkenyl, Rrepresents hydrogen or alkyl, and X represents oxygen or sulphur,possess fungicidal properties.

9 Claims, N0 Drawings SUBSTITUTED 3-PHENYL HYDANTOINS USEFUL ASFUNGICKDES This invention relates to new hydantoin derivatives whichpossess fungicidal properties, to processes for their preparation and tocompositions containing them.

The hydantoin derivatives of the present invention are compounds of thegeneral formula:

wherein Ar represents a phenyl radical or a phenyl radical carrying oneto five substituents, which may be the same or different, selected fromhalogen atoms (preferably chlorine), alkyl and alkoxy radicalscontaining one to four carbon atoms and the trifiuoromethyl radical, R,represents an alkoxy radical containing one to four carbon atoms or agrouping NR R.,, in which R and R are the same or different and eachrepresents a hydrogen atom, an alkyl radical containing one to fourcarbon atoms or an alkenyl radical containing two to four carbon atoms,R represents a hydrogen atom or an alkyl radical containing one to fourcarbon atoms, and X represents an oxygen or sulphur atom.

According to a feature of the invention, the hydantoin derivatives ofgeneral formula I are prepared by the process which comprises reacting acompound of the general formula:

HalCOR,

N-A r I (wherein Hal represents a halogen, preferably chlorine, atom andR, is as hereinbefore defined) with a hydantoin compound of the generalformula:

III

wherein Ar, R, and X are as hereinbefore defined. Generally the reactioncan be carried out in a basic organic solvent such as pyridine or in anorganic solvent such as benzene, chloroform, acetonitrile,dimethylformamide or N-methylpyrrolidone, in the presence of a strongbase such as an alkali metal alkoxide, for example potassium ethoxide,at a temperature between 0C. and the boiling temperature of the reactionmixture.

The starting materials of general formula III can be obtained bycyclisation of an acid or ester of the general formula:

wherein R represents a hydrogen atom or an alkyl radical containing oneto four carbon atoms, and Ar, R and X are as hereinbefore defined. Thecyclisation can generally be effected by heating in an organic solventin the presence of a basic condensation agent.

The compounds of general formula IV can be obtained either: (a) by theaction of an acid or ester of the general formula:

(wherein R,, X and R, are as hereinbefore defined) on an aniline of thegeneral formula:

Ar-NH V! (wherein Ar is as hereinbefore defined), or (b) by the actionof an amino-acid or ester of the general formula:

H,N-cH cooR5 M \II (wherein R and R are as hereinbefore defined) on aphenyl isocyanate or isothiocyanate of the general formula:

Ar-N=C=X Vlll (wherein Ar and X are as hereinbefore defined) accordingto known methods for the preparation of ureas and thioureas.

According to another feature of the invention the hydantoin derivativesof general formula I, wherein R, represents a grouping NR R., in which Rrepresents a hydrogen atom and R represents an alkyl radical containingone to four carbon atoms or an alkenyl radical containing two to fourcarbon atoms, are prepared by the process which comprises reacting anisocyanate of the general formula:

R, N=C=O lX (wherein R,- represents an alkyl radical containing one tofour carbon atoms or an alkenyl radical containing two to four carbonatoms) with a hydantoin compound of general formula III by known methodsfor the preparation of ureas, for example by heating the reactants in anorganic solvent such as benzene or acetone in the presence of a basiccondensation agent such as triethylamine. By the term known methods" ismeant methods heretofore used or described in the literature.

The hydantoin derivatives of general formula 1 obtained by theaforementioned processes may optionally be purified by physical methodssuch as crystallisation, distillation or chromatography.

The hydantoin derivatives of general formula I possess valuablefungicidal properties; they are particularly active against grey moulds(Botrytis cinerea), bean anthracnose (Collectotrichum lindemuthianum)and sclerotinia rot (Sclerotinia sclerotiorum) when used in quantitiesbetween 25 and g. per hectolitre of, for example, water They areparticularly interesting for the treatment of vines, strawberry plants,fruit trees (e.g. peach, apricot and cherry trees) and market gardeningproduce (e.g. vegetables for salads) to control fungal infections.Preferred compounds are those in which Ar represents the phenyl radicalor a phenyl radical carrying one or two substituents selected fromchlorine and fluorine atoms, alkyl radicals containing one to fourcarbon atoms (preferably methyl) and the trifluoromethyl radical, andmore particularly those compounds wherein Ar represents the3,5-dichlorophenyl radical, R, represents a grouping -NR,R, in which Rrepresents a hydrogen'atom and R, represents an alkyl radical containingone to four carbon atoms or an alkenyl radical containing two to fourcarbon atoms (preferably allyl), and R and X are as hereinbeforedefined. Of outstanding importance are 1-propylcarbamoyl-3- (3,S-dichlorophenyl )hydantoin, l-allylcarbamoyl-3- 3(3,S-dichlorophenyl)hydantoin, l-isopropylcarbamoyl-3-(3,S-dichlorophenyl)hydantoin, l-methylcarbamoyl-3-(3,5-dichlorophenyl)hydantoin, l-ethylcarbamoy1-3-(3,S-dichlorophenyl)hydantoin, 1-methy1carbam0yl-3- (3,5-dich1oropheny1)-2-thiohydantoin and 1-ethy1carbamoyl-3-(3,5-dichioropheny1)-2- thiohydantoin.

The present invention also includes within its scope fungicidalcompositions which comprise, as the active ingredient, at least onehydantoin derivative of general formula I in association with one ormore diluents or adjuvants compatible with the hydantoin derivative(s)and suitable for use in agricultural fungicidal compositions. Thesecompositions can optionally contain other compatible pesticides, such asinsecticides or fungicides (e.g. maneb). Preferably the compositionscontain between 0.005 percent and 80 percent by weight of hydantoinderivative.

The compositions may be solid if there is employed a powdered solidcompatible diluent such as talc, ca1- cined magnesia, kieselguhr,tricalcium phosphate, powdered cork, adsorbent charcoal, or a clay suchas kaolin or bentonite. These solid compositions are preferably preparedby grinding the hydantoin derivative with the solid diluent, or byimpregnating the solid diluent with a solution of the hydantoinderivative in a volatile solvent, evaporating the solvent, and ifnecessary grinding the product so as to obtain a powder.

Instead of a solid diluent, there may be used a liquid in which thehydantoin derivative is dissolved or dispersed. The compositions maythus take the form of suspensions, emulsions or solutions in organic oraqueous-organic media, for example aromatic hydrocarbons such as tolueneor xylene, mineral, animal or vegetable oils, anisole, cyclohexanone oracetophenone, or mixtures of these diluents. The compositions in theform of suspensions, emulsions or solutions may contain wetting,dispersing or emulsifying agents of the ionic or nonionic type, forexample sulphoricinoleates, quaternary ammonium derivatives or productsbased on condensates of ethylene oxide, such as the condensates ofethylene oxide with octylphenol, or fatty acid esters ofanhydrosorbitols which have been rendered soluble by etherification ofthe free hydroxy groups by condensation with ethylene oxide. It ispreferable to use agents of the non-ionic type because they are notsensitive to electrolytes. When emulsions are required, the hydantoinderivatives may be used in the form of selfemulsifying concentratescontaining the active sub- EXAMPLE 1 A 22.5 percent (w/v) ethanolicsolution of potassium ethoxide (32 cc.) is added to a suspension of 3-phenylhydantoin (12.3 g.) in benzene (150 cc.). After azeotropicdistillation of the ethanol, methyl chloroformate (6.6 g.) is added andthe reaction mixture heated for 10 minutes under reflux. The benzene isthen evaporated under reduced pressure and the residue is recrystallisedfrom ethanol to yield l-methoxycarbonyl- 3-phenylhydantoin (11 g.)melting at 154C.

3-Pheny1hydantoin, mp. 156C, employed as starting material can beprepared according to the method described by Dains, J. Amer. Chem.Soc., 44, 2312 1- 922).

By proceeding as described above but starting with appropriate compoundsof general formulae II and 111 there are obtained the followingproducts:

Example Product Melting No. Point C 2.1-Methoxycarbony1-3-(3-chloropheny1)- l 5 hydantoin 140 3.1-Ethoxycarbonyl-3-( 3-chlorophenyl hydantoin 128 4.1-Methoxycarbonyl-3-(3,5-dich1oro phenyl)hydantoin 200 Example ProductMelting No. Point (C-) 5. 1-Ethoxycarbony1-3-(31fl5-dich1oropheny1)hydantoin 1 56 6. 1-Ethoxycarbony1-3-( 3-fluorophenylhydantoin 126 7. 1-Ethoxycarbonyl-3-(2,4-dichlorophenyl)-Smethylhydantoin 100 8. 1-Methoxycarbony1-3-(2,4-dich1orophenyl)S-methylhydantoin 1 05 9. l-Methoxycarbony1-3-( 2,4-

dich1orophenyl)hydantoin l 62 10. 1-Methoxycarbony1-3-( 3,5-dimethy1pheny1)- hydantoin 136 EXAMPLE 11 A 22.5 percent (w/v)ethanolic solution of potassium ethoxide (26 cc.) is added to asuspension of 3-(3- chlorophenyl)hydantoin (14 g.) in benzene (200 cc.).After azeotropic distillation of the ethanol, dimethylcarbamoyl chloride(7.2 g.) is added and the reaction mixture is heated for 10 minutesunder reflux. The precipitate which forms is filtered off and thebenzene is evaporated under reduced pressure. The residue obtained iswashed successively with anaesthetic grade diethyl ether (50 cc.) andpetroleum ether (b.p. 50-70- C.; 50 cc.) to yield1-dimethy1carbamoy1-3-(3- chlorophenyl)hydantoin (7.8 g.) melting at152C.

3-(3-Ch1orophenyl)hydantoin, mp. 143C, employed as starting material canbe prepared according to the method described by Dains, J. Amer. Chem.Soc., 44, 2312 (1922).

EXAMPLE l2 Ally] isocyanate (4.5 g.) and triethylamine (5.5 g.) areadded to a solution of 3 3 ,5-

dichlorophenyl)hydantoin 1 1 g.) in acetone 150 cc.). After 30 minutesheating under reflux followed by cooling, the acetone is evaporatedunder reduced pressure. The residue obtained is washed with petroleumether (b.p. 5070C.; 250 cc.) and recrystallised from ethanol to yield1-a11ylcarbamoyl-3-( 3 ,5- dichloropheny1)hydantoin (11 g.) melting at l16C.

3-(3,5-Dichl0rophenyl)hydantoin, mp. 199C, employed as starting materialcan be prepared according to the method described by Dhar, J. Soc. 1nd.Research, 200, (1961).

EXAMPLE 13 Propyl isocyanate (4.6 g.) and triethylamine (5.5 g.) areadded to a solution of 3-(3,5-dichlor0phenyl)- hydantoin (11 g.) inacetone (150 cc.). After 30 minutes heating under reflux followed bycooling, the acetone is evaporated under reduced pressure. The residueobtained is washed with petroleum ether (b.p. 50-70C.; 250 cc.) andrecrystallised from diisopropyl ether to yield 1-propylcarbamoyl-3-(3,5-dichlorophenyl)hydantoin (11 g.) melting at 92C.

By proceeding as described above but starting with appropriate compoundsof general formulae Ill and IX there are obtained the followingproducts:

Example Product Melting No. Point (C. 14. l-lsopropylcarbamoyl-3-( 3-chlorohenyl )hydantoin 109 15. 1-Propylcarbamoyl-3-( 3-chlorophenyl)-hydantoin 90 16. 1-Methylcarbamoyl-3-(3,5-

dichlorophenyl)hydantoin 163 17. 1 Ethylcarbamoyl-3-(3,5-

dichlorophenyl)hydantoin 1 52 18. 1-Methylcarbamoyl-3-(3-chlorophenyl)-5- methylhydantoin l 30 19. l-lsopropylcarbamoyl-3-( 3,5-

dichlorophenyl)hydantoin l 36 20. l-Butylcarbarnoyl-3-(3,5-

dichlorophenyl)hydantoin 1 12 21. 1-lsopropylcarbamoyl-3-( 3,5-

dichlorophenyl)-5-methylhydantoin l 25 22.1-Ethylcarbamoyl-3-(3-fluorophenyl hydantoin l 40 23.l-Propylcarbamoyl-3-( 3-fluorophenyl hydantoin 93 24.1-Methylcarbamoyl-3-(3-trifluoromethylphenyl)hydantoin 120 251-Methylcarbamoyl-3-( 3-fluorophenyl)- hydantoin 207 EXAMPLE 26 Methylisocyanate (3.4 g.) and triethylamine (4 g.) are added to a suspensionof 3-(3,5-dichlorophenyl)-5- methylhydantoin (10.4 g.) in benzene (150cc.). After heating for 1 hour under reflux followed by cooling, thebenzene is evaporated under reduced pressure. The residue obtained iswashed with anaesthetic grade diethyl ether (30 cc.) and petroleum ether(b.p. 50-70- C.; 200 cc.) and recrystallised from ethanol to yield1-methylcarbamoyl-3-( 3 ,5-dichlorophenyl)-5- methylhydantoin (9g.)melting at 137C.

3-(3,S-Dichlorophenyl)-5-methylhydantoin, m.p. l5- 6C., employed asstarting material can be prepared according to the method described byDhar, J. Soc. Ind. Research, 20c, 145 (1961).

By proceeding as described above but starting with with appropriatecompounds of general formulae 111 and 1X there are obtained thefollowing products:

Example Product Melting No. Point 1C.) 27.1-Butylcarbamoyl-3-(3,S-dichlorophenyU-S- methylhydantoin 95 28.1-t-Butylcarbamoyl-3-(3,5-

dichlorophenyl)hydantoin 181 EXAMPLE 29 Methyl isocyanate (3.4 g.) andtriethylamine (5 g.) are added to a solution of 3-(3,5-dimethylphenyl)-hydantoin (10.2 g.) in acetone (120 cc.). After leaving the reactionmixture to stand for 24 hours at a temperature of about 20C., theprecipitate which forms is filtered off and dried in vacuo oversulphuric acid. There is thus obtainedl-methylcarbamoyl-3-(3,5-dimethylphenyl)hydantoin (11 g.) melting at204C.

3-(3,S-Dimethylphenyl)hydantoin, m.p. 128C, employed as startingmaterial can be prepared according to the method described by Dhar, J.Soc. 1nd. Research, 20c, 145 (1961).

EXAMPLE 30 A 22.5 percent (w/v) ethanolic solution of potassuim ethoxide(13 cc.) is added to a solution of 3-phenyl-2- thiohydantoin (6.8 g.) inN-methylpyrrolid-Z-one (150 cc.). After distillation of the ethanolunder reduced pressure, ethyl chloroformate (3.8 g.) is added and thereaction mixture stirred for 5 hours at about 25C. A small amount ofinsoluble material is separated by filtration and the filtrate pouredinto ice-water (500 cc.). The precipitate which forms is filtered offand recrystallised from ethanol to yield l-ethoxycarbonyl-3-phenyl-2-thiohydantoin (4.2 g.) melting at 142C.

3-Phenyl-2-thiohydantoin, m.p. 242C., employed as starting material canbe prepared according to the method described by Aschan, Ber., 17, 424(1884).

By proceeding as described above but starting with appropriate compoundsof general formulae 11 and 111 there are obtained the followingproducts:

Example Product Melting No. Point C. 3 l l-Methoxycarbonyl-3'phenyl-2-thiohydantoin l 32. l-Methoxycarbonyl3-( 3 ,S-dichlorophenylZ-thiohydantoin I 174 EXAMPLE 33 Methyl isocyanate (3.2 g.) andtriethylamine (0.5 cc.) are added to a suspension of3-(3-chlorophenyl)-2- thiohydantoin (7 g.) in benzene cc.). Afterheating for 2 hours under reflux followed by cooling, the precipitatewhich forms is filtered off, washed with diisopropyl ether (2 X 50 cc.)and dried in vacuo over sulphuric acid. There is thus obtained 1-methylcarbamoyl-3-(3-chlorophenyl)-2-thiohydantoin (6.7 g.) melting at170C.

3-(3-Chlorophenyl)-2-thiohydantoin, m.p. 216C, employed as startingmaterial can be prepared according to the method described by Dains, J.Amer. Cham. Soc.,44, 2312 (1922).

By proceeding as described above but starting with appropriate compoundsof general formulae Ill and 1X there are obtained the followingproducts:

Example Product Melting No. Point 7 (C 34. l-Methylcarbamoyl-3-(3,5-dichlorophenyl 2-thiohydantoin 2 10 35.1-Ethylcarbamoyl-3-(3,5-dichlorophenyl)-2- thiohydantoin 2 1 6 EXAMPLE 36 A 22.5 percent (w/v) ethanolic solution of potassium ethoxide (15.4cc.) is added to a solution of 3-(3,5- dichlorophenyl)-2-thiohydantoin(10.4 g.) in dimethylformamide cc.). After removal of the ethanol bydistillation, dimethylcarbamoyl chloride (4.3 g.) is added. Afterleaving the reaction mixture overnight at a temperature of about 20C.,the reaction mixture is poured into water (1,500 cc.) and theprecipitate which forms is extracted with methylene chloride (1,000cc.). After chromatography through a column EXAMPLE 37 In accordancewith a usual technique there is prepared an emulsifiable solution havingthe following composition:

l-propylcarbamoyl-3-(3,5-dichlorophenyl) hydantoin 400 g. Tween 20 g.Atlox 4855 90 g. cyclohexanone-xylene mixture( [-3 by volume) quantityto make up to 1.000 cc.

EXAMPLE 38 In accordance with a usual technique there is prepared anemulsifiable solution having the following composition:

1 -propylcarbamoyl-3-( 3,5 -dichlorophenyl) hydantoin 400 g. Tween 10 g.Atlox 4855 90 g. anisole, quantity to make up to L000 cc.

Tween 20 is a wetting agent which is a condensate of ethylene oxide withfatty acid esters of sorbitol, and Atlox 4855 is an emulsifying agentwhich is a polyoxyethylene derivative of an arylsulphonate.

I claim:

1. A hydantoin derivative of the formula:

wherein Ar represents phenyl or phenyl substituted with one to twosubstituents selected from the group consisting of chlorine, fluorine,alkyl of one to four carbon atoms and trifluoromethyl; R representsalkoxy of one to four carbon atoms or NR R in which R and R representshydrogen, alkyl of one to four carbon atoms or alkenyl of two to fourcarbon atoms; R represents hydrogen or alkyl of one to four carbonatoms; and X represents oxygen or sulphur.

2. A hydantoin derivative according to claim 1 wherein Ar represents3,5-dichlorophenyl; R, represents -NHR in which R represents alkyl ofone to four carbon atoms or alkenyl of two to four carbon atoms; and Rand X are as defined in claim 1.

3. The hydantoin derivative according to claim 1 which islpropylcarbamoyl-3-( 3 ,5 dichlorophenyhhydantoin.

4. The hydantoin derivative according to claim 1 which isl-aIlylcarbamoyl-3-( 3 ,5- dichlorophenyl)hydantoin.

5. The hydantoin derivative according to claim 1 which isl-isopropylcarbamoyl-3-( 3 ,5- dichlorophenyl)hydantoin.

6. The hydantoin derivative according to claim 1 which isl-methylcarbamoyl-3-( 3 ,S- dichlorophenyl )hydantoin.

7. The hydantoin derivative according to claim I which isl-ethylcarbamoyl-3-( 3 ,5- dichlorophenyl)hydantoin.

8. The hydantoin derivative according to claim 1 which isl-methylcarbamoyl-3-( 3 ,5 -dichlorophenyl )-2- thiohydantoin.

9. The hydantoin derivative according to claim 1 which is1-ethylcarbamoyl-3-(3,5-dichlorophenyl)-2- thiohydantoin.

2. A hydantoin derivative according to claim 1 wherein Ar represents3,5-dichlorophenyl; R1 represents -NHR4 in which R4 represents alkyl ofone to four carbon atoms or alkenyl of two to four carbon atoms; and R2and X are as defined in claim
 1. 3. The hydantoin derivative accordingto claim 1 which is 1-propylcarbamoyl-3-(3,5-dichlorophenyl)hydaNtoin.4. The hydantoin derivative according to claim 1 which is1-allylcarbamoyl-3-(3,5-dichlorophenyl)hydantoin.
 5. The hydantoinderivative according to claim 1 which is1-isopropylcarbamoyl-3-(3,5-dichlorophenyl)hydantoin.
 6. The hydantoinderivative according to claim 1 which is1-methylcarbamoyl-3-(3,5-dichlorophenyl)hydantoin.
 7. The hydantoinderivative according to claim 1 which is1-ethylcarbamoyl-3-(3,5-dichlorophenyl)hydantoin.
 8. The hydantoinderivative according to claim 1 which is1-methylcarbamoyl-3-(3,5-dichlorophenyl)-2-thiohydantoin.
 9. Thehydantoin derivative according to claim 1 which is1-ethylcarbamoyl-3-(3,5-dichlorophenyl)-2-thiohydantoin.